Polysialylation controls dendritic cell trafficking by regulating chemokine recognition

Abstract

The addition of polysialic acid to N- and/or O-linked glycans, referred to as polysialylation, is a rare posttranslational modification mainly known to control developmental plasticity of the nervous system. Here we show that CCR7, the central chemokine receptor controlling immune cell trafficking to secondary lymphatic organs, carries polysialic acid. This modification is essential for recognition of the CCR7 ligand CCL21. As a consequence, dendritic cell trafficking is abrogated in polysialyltransferase deficient mice, manifesting in disturbed lymph node homeostasis and unresponsiveness to inflammatory stimuli. Structure-function analysis of chemokine-receptor interactions reveals that CCL21 adopts an autoinhibited conformation, which is released upon interaction with polysialic acid. Thus, we describe a glycosylation-mediated immune cell trafficking disorder and its mechanistic basis.

GATA1-Deficient Dendritic Cells Display Impaired CCL21-Dependent Migration toward Lymph Nodes Due to Reduced Levels of Polysialic Acid

“…It has been suggested that PSA acceptor molecule Neuropilin-2 is the relevant factor involved in this process (see Rey-Gallardo et al [68]), although downregulation in human monocyte-derived DCs did not completely abrogate the capacity to migrate toward CCL21. Recently, it has been shown that CCR7 itself carries PSA modifications (78); however, we do not know at what extent PSA downregulation affects either of the two PSA acceptors in Gata1-KO DC DCs compared with WT. Our study shows that proper sialylation depends on transcriptional programs, in particular downstream of GATA1, which are induced upon DC activation (i.e., LPS stimulation).…”

Transferring the C-terminus of the chemokine CCL21 to CCL19 confers enhanced heparin binding

“…Interestingly, the C-terminus of CCL21 also interacts with polysialic acid (PSA), a rare posttranslational modification recently observed in CCR7 that controls dendritic cell trafficking by regulating chemokine recognition [23]. Mouse dendritic cells expressing polysialylated CCR7 readily migrate in response to CCL21 and a truncated version of CCL21 lacking the extended C-terminus [23].…”

“…Mouse dendritic cells expressing polysialylated CCR7 readily migrate in response to CCL21 and a truncated version of CCL21 lacking the extended C-terminus [23]. This truncated CCL21, called CCL21trunc, lacks residues 80–111.…”

“…This truncated CCL21, called CCL21trunc, lacks residues 80–111. However, cells expressing unmodified CCR7 migrate only in response to CCL21trunc signifying that the PSA modification of CCR7 is essential for receptor activation by full-length CCL21 [23]. Protein NMR shows differences in the spectra of CCL21 and CCL21trunc indicating the two proteins do not have the same conformation [23].…”

Natural search algorithms as a bridge between organisms, evolution, and ecology

“…We need only look within our own bodies to verify both the ubiquity and significance of search. Immune cells use chemical signals to navigate to target tissues; when cells fail to do this, the immune system cannot mount normal responses to infections (12). Development of the vertebrate nervous system depends, in part, on chemotactic search of axonal growth cones (13), and failure of these cells to locate their targets can cause neurological disorders.…”